Electroactive pore

ABSTRACT

Electroactive pores, devices including one or more electroactive pores are described, and methods of delivering therapeutic agents using one or more electroactive pores are described.

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims priority under 35 U.S.C. §119(e)(1) toU.S. Patent Application Serial No. 60/120,879, filed Feb. 18, 1999, andentitled “Drug Delivery Devices Containing An Electroactive Pore”.

FIELD OF THE INVENTION

[0002] The field of the invention relates to electroactive pores, e.g.,for use in the delivery of therapeutic agents.

BACKGROUND OF THE INVENTION

[0003] Certain conditions, such as hypertension, diabetes, hemophiliaand other chronic conditions, can be especially taxing because theyrequire ongoing therapeutic intervention. In many instances, patientscan suffer not only the inconvenience caused by exceedingly frequentdrug administration, but can also risk regular exposure to both toxicand ineffective plasma levels of drugs; toxic levels occurring soonafter the drug is administered and ineffective levels occurring prior tothe next scheduled administration.

[0004] Efforts have been directed toward development ofcontrolled-release preparations such as matrixes, coated granules, ormicrocapsules. In addition, systems for delivery of a certain amount ofdrug per unit time have been developed. Systems that release drugs at aconstant rate (zero-order drug delivery) are known.

[0005] One type of delivery system uses on an infusion pump for drugdelivery.

SUMMARY OF THE INVENTION

[0006] In general, one aspect of the invention features a deviceincluding a member, an electroactive polymer and a biologically activetransfer agent (BETA) associated with the electroactive polymer. Themember has a pore passing therethrough, and the electroactive polymer isdisposed so that when the electroactive polymer has a first state ofcharge a therapeutic agent has a first ability to pass through the pore,and when the electroactive polymer has a second state of chargedifferent from the first state of charge the therapeutic agent has asecond ability to pass through the pore different than the first abilityto pass through the pore.

[0007] As used herein, the term “electroactive polymer” refers to anelectrically conductive polymer. In some embodiments, an electroactivepolymer is a polymer whose conductivity has been modified with one ormore electron acceptor and/or electron donor dopants so that theelectrical conductivity of the polymer is greater than that of theundoped polymer. In certain embodiments, an electroactive polymer ispreferably substantially linear, e.g., contains few, if any, branchpoints or cross-links. Examples of electroactive polymers are disclosedin, for example, U.S. Pat. No. 4,519,938, which is hereby incorporatedby reference.

[0008] In another aspect, the invention generally features a method ofadministering a therapeutic agent. The method includes passing thetherapeutic agent through a device. The device includes a member, anelectroactive polymer and a biologically active transfer agent (BETA)associated with the electroactive polymer. The member has a pore passingtherethrough, and the electroactive polymer is disposed so that when theelectroactive polymer has a first state of charge a therapeutic agenthas a first ability to pass through the pore, and when the electroactivepolymer has a second state of charge different from the first state ofcharge the therapeutic agent has a second ability to pass through thepore different than the first ability to pass through the pore. Themethod optionally includes charging the electroactive pore.

[0009] In a further aspect, the invention generally features a method ofadministering a therapeutic agent. The method includes charging anelectroactive polymer. The electroactive pore is disposed relative to apore so that when the electroactive polymer has a first state of chargethe therapeutic agent has a first ability to pass through the pore, andwhen the electroactive pore has a second state of charge different fromthe first state of charge the therapeutic agent has a second ability topass through the pore different than the first ability to pass throughthe pore. The method also includes passing the therapeutic agent throughthe pore.

[0010] In certain embodiments, the electroactive polymer is at leastpartially disposed within the pore, e.g, entirely disposed within thepore. In some embodiments, the electroactive polymer is at leastpartially disposed outside the pore, e.g., entirely disposed outside thepore.

[0011] The BETA can be associated with the electroactive pore so thatelectronic charge can be transferred between the BETA and theelectroactive pore. The BETA can be associated with the electroactivepolymer by, e.g., crosslinking, ionic bonding, covalent bonding andcombinations thereof.

[0012] In general, the BETA can be an enzyme or a functional derivativeof an enzyme, e.g., glucose oxidase or a functional derivative thereof.

[0013] The device can further include one or more mediators to assist intransferring electric charge, e.g., one or more mediators to assist intransferring electric charge between the member and the electroactivepore and/or one or more mediators to assist in transferring electriccharge between the electroactive pore and an analyte, e.g., glucose.

[0014] The device can further include a reservoir in fluid communicationwith the pore. The reservoir can contain a therapeutic agent. Thereservoir can be constructed from essentially any material(s) that canbe molded to form a cavity. The material(s) can be flexible orinflexible.

[0015] In some embodiments, the first state of charge has a lowerabsolute value than the second state of charge, and the first ability ofthe analyte to pass through the pore is greater than the second abilityof the analyte to pass through the pore.

[0016] The electroactive polymer can include aromatic molecules. Theelectroactive polymer can include a series of alternating single anddouble bonds, e.g. thiophen, phenylene diamine, pyrrole, aniline, orsubstituted derivatives thereof. In some embodiments, the electroactivepolymer is polyaniline.

[0017] In certain embodiments, the electroactive polymer is polyaniline,and the BETA is glucose oxidase.

[0018] The membrane can be a layer of a material.

[0019] The device can further include an attachment member, e.g., anadhesive pad, a belt and/or a strap, to attach the device to a patient.

[0020] The device can also include a relatively positive element, e.g.,an electrode, and a relatively negative element, e.g., an electrode,that together form a bias current within the device.

[0021] In certain embodiments, e.g., when the device is used in vivo,the device can further include a microporous needle that can extend fromthe surface of the skin to the interstitial fluid or to the capillarybed. Similarly, the device can include a cathether that can extend fromthe surface of the skin to the interstitial fluid or to the capillarybed.

[0022] The member can be electrically conductive, e.g., contain anelectrically conductive material, including metals or alloys, such asgold, platinum, palladium, iridium, or combinations thereof. The membercan be formed predominantly of electrically conductive material, and/orthe member can be formed of an electrically non-conductive (orrelatively poorly conductive) material coated with a metal or alloy,e.g., gold, platinum, palladium, or iridium, or a combination thereof.

[0023] The manner in which the electroactive polymer is charged can bevaried. For example, the charge on the electroactive pore can be fixed,variable or cyclical.

[0024] Therapeutic agents that can be used in the devices and methods ofthe invention include, for example, vaccines, chemotherapy agents, painrelief agents, dialysis-related agents, blood thinning agents, andcompounds (e.g., monoclonal compounds) that can be targeted to carrycompounds that can kill cancer cells. Examples of such agents include,insulin, heparin, morphine, interferon, EPO, vaccines towards tumors,and vaccines towards infectious diseases.

[0025] The device can be used to deliver a therapeutic agent to anyprimate, including human and non-human primates. The device can be usedto deliver an agent, e.g., a therapeutic agent to an animal, e.g., afarm animal (such as a horse, cow, sheep, goat, or pig), to a laboratoryanimal (such as a mouse, rat, guinea pig or other rodent), or to adomesticated animal (such as a dog or cat). The animal to which thetherapeutic agent is being delivered can have any ailment (e.g., canceror diabetes). It is expected that the device may be most useful intreating chronic conditions. However, the device can also be used todeliver a therapeutic agent (such as a vaccine) to an animal that is notsuffering from an ailment (or that is suffering from an ailmentunrelated to that associated with the therapeutic agent). That is, thedevice can be used to deliver therapeutic agents prophylactically.

[0026] The devices and methods of the invention can be used toindividually tailor the dosage of a therapeutic agent to a patient.

[0027] The devices and methods of the invention can allow for outpatienttreatment with increased convenience, such as, for example, without theuse of an I.V.

[0028] Devices described herein can be advantageous because they can beused to promote maintenance of the concentration of a therapeutic agentin a patient's plasma within a safe and effective range. Moreover, thedevice can release therapeutic agents in response to the concentrationof an analyte in the patient's system. Thus, the rate of drug deliverycan be appropriate for the patient's physiological state as it changes,e.g., from moment to moment.

[0029] Additional advantages are provided by the design and use of thedevices of the invention. For example, where a BETA are positionedwithin or adjacent one or more pores of a member, the BETA can beprotected from external influences, such as those arising when thedevice is handled and used. This protection can be particularlyadvantageous, e.g., when the BETA is a protein, such as glucose oxidase.In such an event, it can be desirable to maintain the protein's tertiarystructure in order to retain maximal biological activity. In addition,because the device can be easily replaced (e.g., a patient can apply adevice to the skin every day, or every other day) the amount of atherapeutic agent (e.g., insulin) within the device can be limited.Thus, in the unlikely event the device should malfunction, the risk ofserious overdose can be limited. The patient could receive, e.g., atmost, only as much of the therapeutic agent as would be delivered overone or two days of administration. In the event insulin is beingdelivered, in some embodiments the overdose could be limited to aslittle as about 25 units of insulin.

[0030] Other features and advantages of the invention will be apparentfrom the detailed description, the figures and from the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

[0031]FIG. 1 is a cross-sectional view of a device according to oneembodiment of the invention;

[0032]FIG. 2 is a cross-sectional view of a device according to anotherembodiment of the invention;

[0033] FIGS. 3A-3C are cross-sectional views of three states of relativecharge of a portion of a device according to one embodiment of theinvention;

[0034] FIGS. 4A-4F are illustrations of monomers and polymers useful ina device according to the invention;

[0035]FIG. 5 is a schematic representation of the interaction of glucosewith a device according to one embodiment of the invention; and

[0036]FIG. 6 is a perspective exploded view of an embodiment of a testapparatus.

DETAILED DESCRIPTION

[0037]FIG. 1 is a cross-sectional view of an embodiment of a device 10having a member 12 including pores 14. Member 12 is in fluidcommunication with a reservoir 16. In certain embodiments, as explainedbelow, device 10 can be used to administer a therapeutic agent to apatient.

[0038]FIG. 2 is a cross-sectional view of another embodiment of device10 having a member 13, e.g., a microporous needle, including pores 14.Device 10 also includes a reservoir 16 that is in fluid communicationwith member 13. In some embodiments, as explained below, device 20 canbe used to administer a therapeutic agent to a patient.

[0039] FIGS. 3A-3C show cross-sectional views of member 12 having a pore14 with an electroactive polymer 20 and a BETA 22 when electroactivepolymer 20 has different states of charge. Generally, BETA 22,electroactive polymer 20 and member 12 are arranged so that directelectron charge transfer can occur from one of these components to thenext.

[0040] As shown in FIG. 3B, when electroactive polymer 20 has arelatively small state of charge, e.g., the absolute value of the chargeon electroactive polymer 20 is relatively small, the cross-sectionalregion in a direction parallel to a portion of pore 14 that is blockedby electroactive polymer 20 is relatively small.

[0041] As shown in FIGS. 3A and 3C, however, when electroactive polymer20 has a relatively large state of charge, e.g., the absolute value ofthe charge on electroactive polymer 20 is relatively large, thecross-sectional region in a direction parallel to a portion of pore 14that is blocked by electroactive polymer 20 is relatively large.

[0042] Device 10 can be used to administer a therapeutic agent presentin reservoir 16 to a patient by disposing pores 14 in the patient'ssubcutaneous tissue. Device 10 can be advantageously used becausedelivery can be controlled by the state of charge of electroactivepolymer 20 which, in turn, can be controlled by the concentration of ananalyte present in the patient's blood. In some embodiments, the analyteof interest is a species, e.g., a molecule or an ion, present in thepatient's blood that associates with BETA 22. As described below, theassociation between the analyte and BETA 22 can include electrontransfer between BETA 22 and the analyte. Such electron transfer canchange the state of charge of electroactive polymer 20, thereby alteringthe ability of the therapeutic agent to pass through pores 14. Forexample, where one wishes to detect glucose, BETA 22 can be glucoseoxidase, or a functional derivative thereof.

[0043] A. The Member

[0044] Generally, the member can be formed of any material that canserve as a partition between a therapeutic agent and a patient's system,the pores being of sufficient size and density to allow the therapeuticagent to move from one side of the partition (i.e., the side facing thetherapeutic agent) to the other (i.e., the side facing the patient'ssystem). As described further below, this movement can be controlled inpart by an electroactive polymer coating that is applied to the memberin embodiments where such a coating is used.

[0045] The member can be an electrical conductor, a semi-conductor, oran electrical non-conductor. Conductive members include, but are notlimited to, carbon cloth or felt, expanded metal or metal mesh sheets,or differently configured metallic shapes (e.g., cylinders or conesconsisting of metal mesh or metal sheets containing microholes). Themetal can be, e.g., a noble metal, such as gold, platinum, or palladium.The metal can also be a base metal, such as steel, nickel, or titanium.The base metal can be coated with a noble metal, e.g., with gold,platinum, or palladium, or a combination thereof. Conductive alloys canalso be used.

[0046] Materials useful as non-conductive members include, but are notlimited to, silicon, glass, plastic, ceramic, mylar, or membranes, suchas those commercially available from companies that supply materials tomolecular biologists. Such membranes can be sold under tradenames, e.g.,NUCLEOPORE7 (a polycarbonate or polyester membrane containing uniformcylindrical pores), CYCLOPORE7, ANOPORE7, and MILLIPORE7. When onechooses to create reasonably uniform pores (rather than purchase and usea material such as the membranes described above), laser machining canbe performed to create pores having a reasonably uniform diameter anddensity.

[0047] Generally, the member should be thick enough to be practicallyincorporated within a device (i.e., it should be thick enough towithstand application of an electroactive polymer coating withouttearing or being otherwise damaged). In certain embodiments, thethickness of the membrane (or of any other material used as a member)can range, e.g., from about one micrometer to about 20 micrometers(e.g., about 10 micrometers).

[0048] The diameter of the pore can be chosen such that, when coatedwith an electroactive polymer in an uncharged state, it can be open. Thediameter of the pores within the membrane (or within any other materialused as a member) can vary, e.g., from about 0.1 micrometer to about 10micrometers (e.g., from about 1.0 micrometer to about 8.0 micrometers,such as from about 4.0 micrometer to about 6.0 micrometers).

[0049] The pore density (i.e., the number of pores per unit area) canvary and, in certain embodiments, the pore density can be partlydependent on the pore diameter. Generally, the size of the pores andtheir density is inversely proportional (the larger the pores, the lowerthe required density). In some embodiments, pore size and density can beregulated such that an appropriate amount of a therapeutic agent canmove across the member in response to an analyte (as described furtherbelow). In certain embodiments, the pore density can range from about1×10⁵ pores per square centimeter to about 3×10⁸ pores per squarecentimeter.

[0050] Non-conductive members can be coated (e.g., by plating,sputtering, vapor deposition, or the like) with metal, carbon, graphite,or a like material (See Example 1, below). Similarly, a non-conductivemember can be covered with metallic paste. The nonconductive surface caneither be entirely or partially coated with conductive material. Forexample, the conductive material can be patterned around the pores of anon-conductive member by methods known in the art (e.g., by screenprinting, ink jetting, or photolithography).

[0051] In some embodiments, the thickness of the material applied to thenon-conductive surface can be taken into consideration when determiningwhether the diameter of the pore is sufficient to allow passage of atherapeutic agent contained within the device. In certain embodiments,the thickness of the material can be from about 100 nanometers to about500 nanometers.

[0052] In some embodiments, the non-conductive surface can be coated onone side with an electrically conductive material either before or afterthe other side has been coated with an electroactive polymer.

[0053] An electrode can be prepared by using an electrically conductivemember or by immobilizing electrically conductive molecules on thesurface of a non-conductive member. Methods of preparing such electrodesare disclosed, for example, in Zah and Kuwana, (J. Electroanal. Chem.150:645, 1983), Miller, ed. (Chemically Modified Surface in Catalysisand Electroanalysis, ACS Symp. Ser. 192, American Chemical Society,Washington, D.C., 1982), Fujihara (in Topics in OrganicElectrochemistry, A. J. Fry and E. Britton, eds., Plenum Press, NY,1986, at page 255), Lane and Hubberd (J. Phys. Chem. 77:1401, 1978),Merz and Kuwana (J. Electroanal. Chem. 100:3222, 1978), which are herebyincorporated by reference.

[0054] The member itself can be an electroactive polymer formed bysolution coating methods, such as described, for example, in U.S. Pat.No. 4,519,938, which is hereby incorporated by reference.

[0055] The member can be incorporated into a probe, e.g., a probe thatcan be inserted into the body, e.g., into the subcutaneous tissue. Themember that supports the electroactive pore can be fashioned along thesides of a needle (e.g., a microneedle) or a catheter, e.g., a needle orcatheter such as those used in the context of drug delivery, such asdisclosed, for example, in U.S. Pat. No. 5,697,901, which is herebyincorporated by reference.

[0056] In certain embodiments, the microneedle can have a diameter ofabout 300 micrometers.

[0057] In some embodiments, a microneedle suitable for use in the devicecan have a beveled tip and one or more microneedles can be mounted onthe portion of the device that contains a therapeutic agent. In certainembodiments, the beveled tip can taper to a zero diameter along the twomillimeters closest to the tip.

[0058] Microneedles including an interface region and a shaft having amicroflow channel therein can be used and are described in, for example,U.S. Pat. No. 5,855,801, which is hereby incorporated herein byreference.

[0059] B. The Electroactive Polymer

[0060] Devices described herein can include an electrically conductivepolymer. These polymers can function as molecular wires that promoteelectron transfer between the BETA (described below) and anotherelement, e.g., the member (described above). The electroactive polymercan promote electron transfer between the redox center of the BETA andthe member. This transfer can occur in either direction (from the BETA,through the electroactive polymer to the member; or from the member,through the electroactive polymer, to the BETA). In the latter case, theredox state of the BETA can be modulated by an electrode potentialcarried through the electroactive polymer. In the event the BETA is anenzyme, the enzyme's biological activity can depend on the electrodepotential. This mechanism can regulate the activity of the BETA throughelectric stimulation (e.g., the application of a bias potential to thedevice is described below).

[0061] In the unmodified state, the backbone of an electroactive polymercan possess oxidizable and/or reducible moieties. When a voltage isapplied to the electroactive polymer, the backbone can undergo reduction(n-type), thereby attaining a net negative charge. The backbone can alsoundergo oxidation (p-type) thereby attaining a net positive charge. Someelectroactive polymers may contain both reducible and oxidizablemoieties within their backbone. Depending on the voltage applied, theseelectroactive polymers can undergo either reduction or oxidation.

[0062] In some embodiments, to maintain electrical neutrality, counterions and associated water molecules within the surrounding electrolytesolution can move (as in electrophoresis or electroosmosis) into theelectroactive polymer network. This can cause the electroactive polymernetwork to swell, which can reduce the ability of a material, e.g., atherapeutic agent, to pass through the pores. This process can be atleast partially reversible. If the voltage is reversed and the state ofcharge on the electroactive polymer is brought back toward the state ofcharge on the electroactive polymer in its prior state, water andcounter ions can move out of the electroactive polymer and back into theelectrolyte solution. This can cause the electroactive polymer networkto shrink, which can increase the ability of a material, e.g., atherapeutic agent, to pass through the pores. This process is described,for example, in Salehpoor et al., SPIE 3040:192-198, 1997, andpublications cited therein, which are incorporated herein by reference.

[0063] In some embodiments, at a constant applied voltage, theelectroactive polymer can remain in an electrically balanced state,e.g., swollen, until the voltage is reversed and the electroactivepolymer relaxes or shrinks as its state of charge is reduced.

[0064] In certain embodiments, for a molecule that exhibits reversibleor partially reversible redox behavior, e.g., certain BETA, that isassociated with the charged electroactive polymer backbone, electrontransfer between the BETA and the electroactive polymer backbone canoccur. A BETA is associated with an electroactive polymer when it is sodisposed that electric charge can be transferred between the BETA andthe electroactive polymer. Association of the BETA to the electroactivepolymer can involve, e.g., entrapping the BETA within the electroactivepolymer, adsorbing the BETA on the electroactive polymer, ionicallybonding the BETA on the electroactive polymer, physically bonding theBETA on the electroactive polymer, and/or covalently linking the BETA tothe electroactive polymer.

[0065] In some embodiments, association of the BETA with theelectroactive polymer brings the BETA to within, e.g., about 5angstroms, about 10 angstroms, about 20 angstroms, about 40 angstroms,or about 50 angstroms, of the electroactive polymer.

[0066] Where an analyte that specifically oxidizes or reduces the BETAis present in the solution of interest, e.g., the patient's blood,electron transfer can occur from the analyte to the BETA, to theelectroactive polymer and, ultimately, to the member.

[0067] Although not wishing to be bound by theory, it is believed thatin some embodiments if the rate of electron transfer from the BETA tothe electroactive polymer is greater than the rate of electron transferfrom the member to the electroactive polymer (or vice versa), some orall of the charge which thereby accumulates on the electroactive polymerwill be neutralized by the influx of counter ions. As a result, theelectroactive polymer will become less swollen and the ability of amaterial, e.g., a therapeutic agent, to pass through the pores willincrease. As the concentration of analyte generally decreases, theamount of charge transferred to the electroactive polymer decreases,decreasing the ability of a material, e.g., a therapeutic agent, to passthrough the pores. As the concentration of the analyte increases, theamount of charge transferred to the electroactive polymer increases,increasing the ability of the material to pass through the pores. Thiscombination of oxidation/reduction can cause modulation of the abilityof the material to pass through the pores.

[0068] Electroactive polymers can be formed from monomers. For example,electroactive polymers can be formed from cyclic aromatic compounds suchas pyrrole, substituted pyrrole derivatives, thiophene, substitutedthiophene derivatives, furan, indole, isoquinoline, azulene, aniline,and substituted aniline derivatives, or combinations thereof.Polyaniline can be used as an electroactive polymer in batteryelectrodes, such as disclosed in, for example, Kitani et al., J.Electrochem. Soc. 133:1069-1073, 1986, which is hereby incorporated byreference.

[0069] In certain embodiments, the electroactive polymer can be coatedas follows. A buffer solution containing one molar Bes, pH 7.0 or 7.4phosphate buffered saline is formed. Pyrrole is added to the buffer andstirred until it dissolved. The concentration of pyrrole is from aboutfive volume percent to about six volume percent. Glucose oxidase (aboutone volume percent to about three volume percent) is added and stirreduntil it dissolved. Other proteins can optionally be added (e.g., BSAand/or Byco C). The buffer, enzyme and pyrrole solution is then placedin a cell with a reference electrode (e.g., a silver/silver chloridereference electrode), a counter electrode (e.g., a platinum electrode),and a working electrode (e.g., a platinum electrode). The solution inthe cell is not stirred. A potential of from about 0.4V to about 0.6Vrelative to the silver/silver chloride reference is applied to theplatinum electrode until from about 200 microcoulombs to about 3000microcoulombs passed, at which point the applied voltage is turned off.The working electrode is then removed, rinsed in phosphate buffer anddried in a 60° C. oven for from about 15 minutes to about 30 minutes.Typically, a membrane solution containing polyurethane dissolved intetrahydrofuran is dip coated onto the wire. The electrode with thepolyurethane coat is dried at room temperature for about 15 minutes,then at 60° C. oven for about 15 minutes. The electrode is then testedin a buffer solution to which incremental levels of glucose is added toobtain a dose response curve.

[0070] In some embodiments, the electroactive polymer can be stable inboth air and water.

[0071] In embodiments, pyrrole is used as the monomer for producing anelectrically conducting polypyrrole coating.

[0072] Examples of certain monomers and polymers that can be used areshown in FIGS. 4A-4F.

[0073] In FIG. 4A, where X is SH, the monomer is thiophene; where X isO, the monomer is furan; when X is NH and R₁ and R₂ are H, polypyrroleis formed.

[0074] An indole monomer is shown in FIG. 4B.

[0075] An isoquinoline monomer is shown in FIG. 4C.

[0076] The aromatic compound shown in FIG. 4D is aniline (when R1, R2,R3, and R4 are H), which can be assembled to form linear or branchedpolymers.

[0077] Four examples of linear polyanilines (where R₁ to R₅ are H) areshown in FIG. 4E.

[0078]FIG. 4F shows two examples of mixed state polymers.

[0079] In addition to the R groups present in the monomers describedabove, substituted polymer derivatives can be formed by using, forexample, one or more of the following R groups: —OCH₃, —OR, —CH₃, —C₂H₅,—F, —Cl, —Br, —I, —NH₂, —NR, —NHCOR, —OH, —O—, —SR, —OCOR, —NO₂, —COOH,—COOR, —COR, —CHO, —CN, —(CH₂)_(n)—CH₃ (e.g., where n is from 0 to 12).

[0080] The electroactive polymer can be applied to the member byphysical association. The association can be one which allows theelectroactive polymer to adhere to the member. For example, the membercan be dipped in a solution containing the electroactive polymer.Similarly, an electroactive polymer-containing solution can be sprayedonto the member.

[0081] Alternatively, the electroactive polymer can be deposited bypolymerization of monomers dissolved in solution, e.g, by oxidizingchemical polymerization. For example, one can place a pyrrole solutionin water (e.g., from about 0.3 molar to about 0.8 molar pyrrole) on oneside of the member (e.g., a membrane) and an iron(III) chloride solutionin water (e.g., from about 1.5 molar to about 2.5 molar) on the other.The pyrrole can be be polymerized by contacting the two solutions withthe member (e.g., the pores of the member).

[0082] As known to those skilled in the art, the time for polymerizationcan vary depending upon the particular materials used. For example, atime period of from about two minutes to about 10 minutes can be used.In certain embodiments, time periods appreciably longer than 10 minutescan result in formation of essentially nonporous members, which canlimit its usefulness in the device of the invention.

[0083] The polymerization reaction can be stopped, for example, byrinsing with water or a phosphate buffered saline, e.g., PBS, pH 6.5.

[0084] In some embodiments, an electrochemical reaction can bring aboutpolymerization on the member. For example, the first step inelectrochemical polymerization of pyrrole can be generation of a radicalcation at the anode. Chain propagation can then proceed by reaction oftwo radical cations, pairing the spins and elimination of two protons toproduce the neutral dimer. At the potentials used to oxidize themonomer, it can be possible to oxidize the dimer and higher oligomers tothe corresponding radical cation. Chain propagation can continue byreaction of the oligomer radical cation primarily with the radicalcation of the monomer, which can be present in high concentration in theregion of the anode. As the chain grows, the pyrrole oligomer can becomeinsoluble and precipitate out on the electrode, e.g., the member, wherethe chain can continue to grow until the oligomer radical cation becomestoo unreactive or until it becomes prevented from reacting by stearichindrance.

[0085] The polypyrrole coat formed by electrochemical synthesis from asolution of pyrrole and sulfuric acid in water can be in the oxidationstate of one positive charge for three to four pyrrole rings. Itsconductivity can be about 8 S/cm. The coat made in a nonaqueous mediumcontaining pyrrole and N(Et)₄BF₄ in CH₃CN can be in the oxidation stateof one positive charge for four to five pyrrole rings, with aconductivity of about 100 S/cm.

[0086] Other materials can be used in a similar fashion, such asthiophene, furan, indole, and azulene, which can also undergoelectrochemical polymerization and oxidation to yield oxidized polymersof varying conductivities.

[0087] Aniline can also be electrochemically polymerized in an acidicaqueous solution to yield a conductive polyaniline membrane on thesurface of a member. For example, electrochemical polymerization can beperformed in a glass electrochemical vessel equipped with threeelectrodes (a working electrode, a counter electrode, and a referenceelectrode). The potential of the working electrode can be controlled at+1.2 versus a reference electrode (e.g., a Ag/AgCl reference electrode)with a potentiostat, and an aqueous solution containing aniline and aBETA (e.g., an enzyme) can be added to the vessel. Electrolysis cancontinue until a fixed charge is passed. The total charge passed cancontrol the thickness of the electroactive polymer coating on themember. This procedure demonstrates that in certain embodiments, theelectrochemical polymerization and deposition of monomers can be carriedout in the presence of a BETA.

[0088] The BETA glucose oxidase has been successfully entrapped inpolyaniline polymerized on the surface of a platinum member and shown toretain its biological activity. Moreover, the membrane formed ispermeable to small molecules such as oxygen and H₂O₂ but not to largermolecules. Accordingly, when a device contains a member, polyaniline(electroactive polymer), and glucose oxidase (BETA), glucose levels canbe monitored by monitoring the change in the oxygen-reducing current orhydrogen peroxide oxidizing current that is produced upon consumption ofoxygen, which occurs subsequent to the interaction between glucose andglucose oxidase. (See FIG. 5).

[0089] When a polymerization reaction is complete, the extent ofpolymerization can be assessed, if desired, by examining the coatedmember with a scanning electron microscope. The thickness of theelectroactive polymer layer within the pores can depend, for example, onthe diameter of the pores. In some embodiments, a device having poresthat are substantially closed will prevent at least 80% (e.g., 85%, 90%,95%, or even 99%) of the therapeutic agent contained therein fromexiting the device under physiological conditions of use (i.e., whenapplied to a patient) within a 24 hour period of time.

[0090] The redox potential of a polymer is normally lower than that ofthe corresponding monomer(s) from which it was formed. Thus, in someembodiments, synthesized polymers can be electroconductive withoutfurther doping.

[0091] C. The BETA

[0092] A biological molecule that is capable of acting as a BETA can beassociated with the electroactive polymer. Suitable BETA generallyinclude enzymes, and functional derivatives thereof. BETA can beincorporated into the devices described herein by methods similar tothose used to incorporate monomers (thereby forming a conductive polymernetwork).

[0093] BETA can be selected, for example, from among those thatparticipate in one of several organized electron transport systems invivo. Examples of such systems include respiratory phosphorylation thatoccurs in mitochondria and the primary photosynthetic process ofthyrakoid membranes.

[0094] BETA can specifically interact with a metabolite or analyte inthe patient's system. For example, BETA-analyte pairs can includeantibody-antigen and enzyme-member.

[0095] Redox enzymes, such as oxidases and dehydrogenases, can beparticularly useful in the device. Examples of such enzymes are glucoseoxidase (EC 1.1.3.4), lactose oxidase, galactose oxidase, enoatereductase, hydrogenase, choline dehydrogenase, alcohol dehydrogenase (EC1.1.1.1), and glucose dehydrogenase.

[0096] The BETA can be associated with the electroactive polymer bytechniques known in the art. The association can be such that electronscan flow between the BETA and the electroactive polymer. In addition tothe methods described above, the BETA and the electroactive polymer canbe associated, e.g., by entrapment, crosslinking, ionic bonding, orcovalent bonding. The member to which an electroactive polymer has beenaffixed can be treated with a redox enzyme-containing solution by, e.g.,exposing the member-polymer to the solution, with agitation, at 2 EC to10 EC for at least 5 minutes and preferably up to 30 minutes. Theconcentration of the redox enzyme in solution can vary and, in certainembodiments, is preferably about 5 mg/ml. Following this treatment, theprepared device can be dried overnight in a desiccator over CaCl₂.

[0097] Where glucose oxidase is the BETA, it can be present at fromabout 0.02 U per square centimeter to about 0.2 U per square centimeterof surface (where 1 unit is the amount of enzyme required to oxidize 1imol of â-D-glucose per minute at pH 5.1 and at a temperature of 35 EC).

[0098] Devices described herein can exhibit specificity for a givenanalyte; and the specificity can be imparted by the selectiveinteraction of an analyte (e.g., glucose) with the BETA (e.g., glucoseoxidase or glucose dehydrogenase).

[0099] D. The Bias Potential

[0100] A bias current or voltage, e.g., a fixed, variable, or cyclicalcurrent or voltage, can be applied to the device (e.g., to the surfaceof the member). The bias potential can be determined empirically.Typically, the magnitude of the applied voltage ranges from ±10 volt vs.Ag/AgCl. The magnitude of the current can range from 1.0 picoamp (10⁻¹²amps) to 1.0 amp (e.g., the current can range from 100 picoamps to 0.1amp). When such a field is established, the device can emulate a workingelectrode (or indicator electrode) in an electrochemical cell consistingof a cathode and an anode, with or without a reference electrode. Acounter electrode can, e.g., be constructed from carbon, graphite,platinum, silver, like metals, or mixtures thereof. A referenceelectrode can, e.g., be constructed from silver or silver chloride.

[0101] At a given current or voltage, the change in the redox state ofthe electroactive polymer will be proportional to the amount of analytethat interacts with the BETA (the amount of the analyte that interactswith the BETA is, in turn, proportional to the concentration of ananalyte, e.g., an analyte in a patient; e.g., the higher theconcentration of glucose in a patient's bloodstream, the more glucosewill interact with glucose oxidase in the device).

[0102] In one embodiment, one can detect (and thereby monitor) theconcentration of an analyte in a patient by examining the state of thedevice (i.e., the change in the bias potential).

[0103] The bias potential may be set to maintain a constant release oftherapeutic agent from the reservoir within the device (such as wouldmaintain a basal level of an analyte). Constant release can be achievedby determining the electrochemical properties of the BETA-electroactivepolymer combination. For example, by performing solution experimentsusing cyclic voltammetry, redox potentials can be obtained. The currentmaximum in a cyclovoltammetric peak indicates the potential at which thereduction or oxidation reaction is proceeding at its maximum diffusionlimited rate. When the potential across the device is set at this value,the on/off actuation of the device may be so rapid that little drug isdispensed. However, if the bias potential is set below the diffusionlimited value, charge accumulation within the device can occur. Underconditions where charge accumulation occurs, the opening within thepores is increased, allowing for greater release of the therapeuticagent contained within the device into a patient's system. As theaccumulated charge decreases, the opening within the pores is decreased,until the level of the basal current is reached.

[0104] The bias potential can be controlled by a computer, e.g., amicroprocessor within the device or elsewhere (e.g., at a remotelocation).

[0105] E. The Reservoir and Ejection of Therapeutic Agents

[0106] A device described herein can also have a reservoir forcontaining a therapeutic agent. The reservoir may take the form of achamber that can be expanded or contracted; expanded when filled with atherapeutic agent and contracted to dispense or expel the agent.Typically, the reservoir will accommodate 0.2-10.0 ml of a solution orsuspension containing a therapeutic agent (e.g., the reservoir cancontain 0.4, 0.5, 1.0, 2.5, 5.0 or 7.5 ml of such a solution). Thereservoir and therapeutic agent can be chosen such that the devicecontains not more than 1, 2, 3, 5, or 10 days supply of the agent.

[0107] The reservoir can also be divided so that an agent, e.g., atherapeutic agent, can be stored in one compartment and a solution,e.g., an aqueous solution such as a saline solution can be stored in asecond compartment. The division between the cavities or compartments inthe reservoir would then be broken prior to use so that the therapeuticagent comes into contact with the solution.

[0108] Optionally, the device can include a pump or similar device forpositively ejecting a therapeutic agent from the reservoir in which itis stored. The pump can be, e.g., a mechanical or partially mechanicaldevice, as described below, that exerts pressure on the reservoir sothat the therapeutic agent therein is ejected through the pores of thedevice, into the patient's system. The pressure exerted by the pump canbe regulated by the current generated when an analyte specificallyinteracts with a BETA. For example, in a device designed for treatmentof diabetes mellitus, the higher the patient's blood glucose level, themore glucose will interact with glucose oxidase or glucose dehydrogenasewithin the device, and the greater the current generated by the transferof electrons from glucose, to glucose oxidase, to the electroactivepolymer within the membrane, to the electrically conductive memberbeneath. The greater this current, the greater the signal conveyed tothe pump, and the more insulin will be ejected from the reservoir intothe patient's system. As the patient's blood glucose levels fall inresponse to the newly presented insulin, the current generated acrossthe device will fall, and the pump will, accordingly, drive less insulininto the patient's system.

[0109] The source of the pressure exerted by the pump can be anelectrical actuator, such as a piston whose speed and/or stroke ismodulated, as described above, by the concentration of an analyte in thepatient's system. Alternatively, the piston can be driven by ananalyte-modulated chemical or physiochemical reaction (e.g.,electrolysis of H₂O) that produces a gas that drives the piston.

[0110] Osmotic Pumps

[0111] Elementary osmotic pumps are known in the art (see, e.g.,Theeuwes, Drug Dev. & Indust. Pharm. 9:1331-1357, 1983; Boudier, Trendsin Pharmacol. Sci. pp. 162-164, April 1982, which are herebyincorporated by reference). These pumps were developed in response tothe need to maintain the concentrations of drugs in a patient's plasma,particularly those that require chronic administration, within a safeand effective range. Conventionally, patients receive their medicationby bolus administration (e.g., by injecting or otherwise administering aset amount of a drug). Immediately after such administration, the plasmalevel of the drug can exceed the maximum level for safety. But beforethe next scheduled administration, the level can fall below the minimumlevel required for effectiveness. As a result, patients are repeatedlyexposed to both toxic and ineffective concentrations of drugs. The ratioof these two levels (the maximum level for safety and the minimum levelfor effectiveness) is known as the therapeutic index. While thesefluctuations can be minimized by dosing at frequent time intervals, therequired regimen can be extremely inconvenient for the patient(particularly where the drug has a short half-life).

[0112] Examples of delivery systems in which osmotic pressure is thedriving force behind drug release include PROGESTASERT7, a contraceptivesystem that releases progesterone to the uterine lumen at a rate of 65microgram per day for one year, and OCUSERT7, an ocular system thatreleases pilocarpine to the eye at rates of 20 or 40 micrograms/hour forone week. Similarly, an elementary osmotic pump, such as described byTheeuwes (supra) can be used to dispense therapeutic agents into thegastrointestinal (GI) tract at a rate independent of external factorssuch as GI tract pH and motility. These systems illustrate two of themost prominent advantages of osmotic minipumps: constant and prolongeddelivery of a drug at a predetermined rate and the ability to targetdelivery to a particular tissue or organ.

[0113] Structurally, osmotic pumps can include a solid core,semipermeable membrane and an orifice for drug delivery. Osmosis is theforce driving expulsion of a drug from the device: water imbibed, e.g.,from the environment, crosses the membrane at a controlled rate andcauses the drug solution to exit through the delivery orifice. Deliveryrate is controlled by osmotic properties of the core and membrane area,its thickness, and permeability to water.

[0114] In another embodiment, the change in the charge of theelectroactive polymer within the pores of the device can serve as aself-regulating osmotic pump. Charge neutralization can occur bymigration of water and ions into and out of an electroactive polymer(i.e., by doping and undoping), thereby creating an osmotic pumpingaction.

[0115] Expulsion of a Therapeutic Agent from the Device

[0116] When one or more therapeutic agents are contained within thedevice and have access to the pores of the device (the agent(s) will bepositioned so that they can move through the pores and into a patient'sbody), modulation of the diameter of the pore can, alone, be sufficientto allow sufficient movement of the agent(s) into the outer electrolytesolution.

[0117] In another embodiment, the modulated current generated bycharging the electroactive polymer in response to the level of analytecan be used to control an electromechanical pump that, when activated,forces the agent(s) through the open pore and into the outer electrolytesolution. Thus, in effect, the analyte level modulates both the poreopening and the pumping force. This double feedback redundancy is anadded safety feature of the system. If, for some reason, the pump failedto shut off at the appropriate time, the declining analyte concentrationwould cause the pore to close. When pressure within the reservoircontaining the therapeutic agent(s) increases to a pre-set level,electrical contact to the pump is shut off until the pressure falls backto within its normal range of operation. If the pore fails to close asthe analyte level falls (in response to infusion of the therapeuticagent(s)) the current generated by charging the electroactive polymerwill also fall and the pump will gradually shut down.

[0118] If electron transfer between the BETA and the electroactivepolymer is slower than between the member and the electroactive polymer,and if the applied potential across the polymer network is pulsed, thenpulsing of the pore opening can also be achieved. During the “off”period, all or part of the polymer can be reduced or oxidized by theBETA so that the polymer returns to its virgin state. This opens thepore. The amount of charge transferred between pulses determines thesize of the pore opening. When the potential is again turned on, thepolymer is again fully charged and it closes. In effect, this on/offcycling can cause a pumping action. Thus, the pore size and the pumpingaction are modulated by the amount of analyte in the outer electrolytesolution. If a therapeutic agent was dissolved and stored on the innerside of the pore, pulsing of the pore could force the agent from insidethe pore to the outer electrolyte solution. If the level of analyte wasmodulated by the amount of drug in the outer solution, the combinationof the processes above would constitute a self-regulating drug deliverydevice. As in the case described above, pumping of the drug could bedone through use of a conventional electromechanical pump.

[0119] In another embodiment, self-regulated pumping can be achieved bystoring therapeutic agent(s) within a collapsible reservoir. As the poreopen, the natural tendency would be for the drug to move from a solutionof high concentration to a solution of low concentration untilequilibrium is achieved. Modulation of the pore opening may also be usedto regulate the amount of water imbibed by a collapsible reservoirsurrounding the drug reservoir. Water imbibed when the pore is opencauses the volume within the osmotic reservoir to increase, therebyforcing the therapeutic agent(s) out of the device.

[0120] Attachment of a Device

[0121] The device itself can be used in a number of environments. It canbe used in vivo or ex vivo (e.g., in a cell culture environment). In theevent the device is used in vivo it may be wholly or partiallyinternalized in a patient's body. For example, the device can include anadhesive component and a probe that extends beneath the body surface.When a portion of the device is worn externally, it can be attached tothe patient by a belt, strap, or adhesive (e.g., it can be attached tothe patient's skin by an adhesive patch). In some instances, an adhesiveand a second security device (e.g., a belt or strap) can be used.

[0122] The amount of therapeutic agent carried within the device canvary. The amount can include less than 1, less than 2, less than 5 orless than 10 days supply of a therapeutic agent or agents.

[0123] Test Apparatus

[0124]FIG. 6 shows a test apparatus 60 that can be used to determinewhether a candidate system will be useful for delivering a therapeuticagent as described herein. Device 60 includes an upper housing 62, anseal 64 (e.g., an o-ring seal), an electrically conductive sheet 66(e.g., a platinum sheet) having a hole 67, a seal 68 (e.g., an o-ringseal), a spacer housing 70, a seal 72 (e.g., an o-ring seal), anelectrically conductive sheet 74 (e.g., a platinum sheet), a seal 76(e.g., an o-ring seal), and a lower housing 78 with a flow tube inlet 80and a flow tube outlet 81. Sheet 74 contains a region 75 with pores thatare filled with an electroactive polymer and BETA. The electroactivepolymer is associated with the pores (e.g., having a diameter of fromabout three micrometers to about five micrometers), and the BETA isassociated with the electroactive polymer.

[0125] A solution containing a material of interest (e.g., a therapeuticagent) is disposed in the upper, housing and a solution containing ananalyte flows from flow tube inlet 80 to flow tube outlet 81. As theanalyte-containing solution flows through tube 80, the analyte caninteract with the BETA (e.g., via a redox reaction).

[0126] If a redox reaction between the BETA and analyte occurs, the sizeof the electroactive polymer decreases, increasing the ability of thesolution contained in upper housing 62 to pass through the pores insheet 74. At the same time, the electrical current formed by thereaction can be used to control a mechanism for increasing the pressurehead on the solution contained in upper housing 62 (e.g., by controllinga pump, or by controlling the bias on a platinum/NAFION electrode plateon the upper portion of housing 62 which passes oxygen formed by waterelectrolysis caused by the electrical current), which also increases theability of the solution to pass through the pores in sheet 74. This canincrease the concentration of the material of interest (e.g.,therapeutic agent) in the solution passing through flow tube outlet 81,which can be measured using techniques known to those skilled in the art(e.g., spectrophotometry).

[0127] If a redox reaction between the BETA and analyte does not occur,the ability of the solution contained in upper housing 62 to passthrough the pores in sheet 74 should not increase, and an increase inthe concentration of the material of interest passing through outlet 81should not increase as a result of an interaction between the analyteand the BETA.

EXAMPLES Example 1

[0128] Coating a NUCLEOPORE7 Membrane with Platinum

[0129] A NUCLEOPORE7 membrane is pressed against the cooling plate of anEdwards S150B sputtercoater using a template with an opening that isslightly smaller than the diameter of the membrane. Platinum is then beapplied to a thickness of 100-400 nm by sputtering under an argonpressure of 8 nBar and using a sputtering current of 50 mA. Thethickness of the layer can be measured with an Edwards FTM5 unit.

Example 2

[0130] Oxidizing Chemical Polymerization of Pyrrole

[0131] Pyrrole is polymerized in the pores of a NUCLEOPORE7 membrane (25mm in diameter) by allowing about 4 ml of an aqueous 2 M FeCl₃ solutionand about 1 ml of an aqueous 0.6 M pyrrole solution to precipitate. Thisis carried out by positioning an injection syringe, which is filled withthe iron chloride solution, vertically and mounting a standard membraneholder thereon. The membrane rests on the holder and can be weighteddown with a rubber ring. The level of oxidizing iron (III) chloridesolution in the syringe is raised until it just touches the membraneresting on the holder, and 1 ml of the pyrrole solution is applied tothe membrane. The polymerization time is measured from the time thissolution is applied. For NUCLEOPORE7 membranes having a diameter of 0.8im and a pore density of 3×10⁷ pores/cm², the polymerization can becontinued for 1-10 minutes, after which time the membrane can be removedfrom the holder and rinsed with water or a phosphate buffer.

Example 3

[0132] Immobilization of Glucose Oxidase

[0133] Enzyme is immobilized on members prepared as described inExamples 1 and 2, and having an original pore diameter of 800 and 1000nm. For enzyme immobilization, such a platinum- and pyrrole-coatedmember can be added to about 4 ml of a 5 mg/ml solution of glucoseoxidase and incubated with shaking on a Gyratory Shaker Model G2 (NewBrunswick Scientific). The immobilization reaction is continued for atleast 30 minutes at 4EC. The membrane (serving as the member) can thenbe rinsed in PBS (pH=6.5) and dried overnight at 4 EC. Drying takesplace in a desiccator under normal pressure and in the presence ofCaCl₂.

Example 4

[0134] Testing the Device

[0135] The activity of glucose oxidase, following application to thepolymer-coated member as described above, is determined with athree-electrode cell containing 15 ml 0.1 M phosphate buffer (pH=6.5), 5mM benzoquinone, and 0.5 M glucose. The glucose solution is allowed tomutarotate for at least 24 hours. The is carried our using a Pt rotarydisc electrode (RDE) provided with an Electrocraft Corporation ModelE550 motor and an E552 speed control unit.

[0136] A potential of 0.350 V (Ag/Ag⁺ reference) is applied to the Ptworking electrode, which is rotated at 3000 rpm. A spiral-shaped Ptelectrode can be used as an auxiliary electrode, and the solution isflushed with argon before each test. During the test, the solution isblanketed with argon.

[0137] Electrochemical measurements are carried out using an Autolabpotentiostat, which is controlled by a personal computer and GeneralPurpose Electrochemical System (GPES) software (Eco Chemie, TheNetherlands). The current output is recorded using a Yew 3056 penrecorder. The actual test is carried out by recording the current outputof the RDE on submerging the sample membrane in the abovementionedsolution.

[0138] Various modifications and alterations to the above-describeddevices and methods are also contemplated by the invention. For example,in certain embodiments, a mediator can be used to assist in transferringelectric charge between the membrane and the electroactive polymerand/or between the analyte and the electroactive polymer. Such mediatorsare well known to those skilled in the art and are disclosed, forexample, in, for example, U.S. Pat. Nos. 5,126,034; 5,509,410;5,628,890; 5,658,444; 5,682,884; 5,710,011; 5,727,548; and 5,849,174,and Szentrimay et al., ACS Symposium Series 438, chapter 9, p. 143, 1977(D. T. Sawyer, ed.), which are hereby incorporated by reference.

[0139] In some embodiments, a device can include more than one member.In these embodiments, one or more of the members can include one or morepores, and one or more of the pores can include an electroactive polymerwith or without a BETA associated thereto.

[0140] While the foregoing discussion has generally related to the useof one electroactive polymer in a device, more than one electroactivepolymer can also be used. Similarly, while the foregoing discussion hasgenerally related to the use of one BETA, more than one BETA can also beused. In certain embodiments, the device can contain more than oneelectroactive polymer and more than one BETA.

[0141] It is to be understood that while certain embodiments of theinvention have been described herein, the invention is not limited bythis description. Other embodiments are in the claims.

What is claimed is:
 1. A device, comprising: a member having a porepassing therethrough; an electroactive polymer disposed so that when theelectroactive polymer has a first state of charge a therapeutic agenthas a first ability to pass through the pore, and when the electroactivepore has a second state of charge different from the first state ofcharge the therapeutic agent has a second ability to pass through thepore different than the first ability to pass through the pore; and aBETA associated with the electroactive polymer.
 2. The device of claim1, wherein the electroactive polymer is at least partially disposedwithin the pore.
 3. The device of claim 1, wherein the electroactivepolymer is at least partially disposed outside the pore.
 4. The deviceof claim 1, wherein the BETA is associated with the electroactive poreso that electronic charge can be transferred between the BETA and theelectroactive pore.
 5. The device of claim 1, wherein the BETA isassociated with the electroactive polymer by an association selectedfrom the group consisting of crosslinking, ionic bonding, covalentbonding and combinations thereof.
 6. The device of claim 1, wherein theBETA comprises an enzyme.
 7. The device of claim 1, wherein the BETAcomprises glucose oxidase.
 8. The device of claim 1, further comprisinga mediator.
 9. The device of claim 8, wherein the mediator mediatescharge transfer between the electroactive pore and the member.
 10. Thedevice of claim 8, wherein the mediator mediates charge transfer betweenthe electroactive pore and an analyte.
 11. The device of claim 1,further comprising a reservoir in fluid communication with the pore. 12.The device of claim 11, further comprising a therapeutic agent disposedwithin the reservoir.
 13. The device of claim 1, wherein the first stateof charge has a smaller absolute value than the second state of charge.14. The device of claim 13, wherein the first ability of the analyte topass through the pore is greater than the second ability of the analyteto pass through the pore.
 15. The device of claim 1, wherein theelectroactive polymer comprises a polymer comprising a componentselected from the group consisting of thiophen, derivatives of thiopen,phenylene, derivatives of phenylene, diamine, derivatives of diamine,pyrrole, derivatives of pyrrole, aniline, derivatives of aniline, andcombinations thereof.
 16. The device of claim 15, wherein the BETAcomprises glucose oxidase.
 17. The device of claim 1, wherein themembrane is a layer of a material.
 18. A method of administering atherapeutic agent, comprising: passing the therapeutic agent through adevice, comprising: a layer of a material having a pore passingtherethrough; an electroactive polymer disposed so that when theelectroactive polymer has a first state of charge a therapeutic agenthas a first ability to pass through the pore, and when the electroactivepore has a second state of charge different from the first state ofcharge the therapeutic agent has a second ability to pass through thepore different than the first ability to pass through the pore; and aBETA associated with the electroactive polymer.
 19. The method of claim18, further comprising charging the electroactive polymer.
 20. Themethod of claim 19, wherein charging the electroactive polymer includesbiasing the electroactive polymer.
 21. The method of claim 20, whereinthe bias is selected from the group consisting of a fixed bias, avariable bias and a cyclical bias.
 22. A method of administering atherapeutic agent, comprising: charging an electroactive polymer, theelectroactive pore being disposed relative to a pore so that when theelectroactive polymer has a first state of charge the therapeutic agenthas a first ability to pass through the pore, and when the electroactivepore has a second state of charge different from the first state ofcharge the therapeutic agent has a second ability to pass through thepore different than the first ability to pass through the pore; andpassing the therapeutic agent through the pore.
 23. The method of claim22, wherein charging the electroactive polymer includes biasing theelectroactive polymer.
 24. The method of claim 23, wherein the bias isselected from the group consisting of a fixed bias, a variable bias anda cyclical bias.